Fragmented early-life experiences, aberrant circuit maturation, emotional vulnerabilities

这个跨学科的中心更新建议解决了影响认知的早期环境信号 以及这些信号调节大脑发育的机制 情绪和认知的神经回路我们已经发现母性信号的模式 影响认知和情感发展：具体来说，不可预测和碎片化的模式， 母亲的情绪和行为（FRAG）在胎儿期开始的风险增加内化症状 这预示着从婴儿期到青春期的快感缺失和认知障碍。重要的是， FRAG是先前确定的影响因素（如母亲抑郁、焦虑、敏感）的补充。 在这个修订后的续签申请中，我们受益于审查员的建议，并利用了一批儿童 在最初的奖励期间，我们对他们进行了前所未有的产前和产后暴露 历史，以检验FRAG是一种影响心理健康结果的新型逆境的假设 通过大脑回路的异常成熟扩展我们现有的认知和情感评估， 考虑到暴露和评估时的性别和年龄是重要的变量，我们将强调快感缺失， 一种新的FRAG结果在不同物种中被鉴定出来，作为一种重要的跨诊断 精神疾病中的维度实体我们将检查3-6岁的快感缺乏的早期表现 儿童使用维度RDoC方法，确定新的母体信号，增加其风险， 表达，并确定机制和生物标志物，分别集中在破坏正常大脑 电路发展和表观遗传特征。因此，我们将利用我们最先进的神经成像技术， 个体内甲基化组学和新的评估工具来测试以下假设：（1）早期生命 暴露于支离破碎和不可预测的母亲信号会增加3至6岁儿童快感缺乏的风险 孩子(2)暴露于支离破碎和不可预测的早期家庭环境会增加 3至6岁儿童的快感缺乏。(3)早期生活暴露于支离破碎和不可预测的母亲 和环境信号增加了儿童早期快感缺乏的风险， 快乐/奖励大脑回路和甲基化改变（签名）在两个配对的样本，从相同的 婴儿将提供这种风险预测性生物标志物。

This trans-disciplinary Center renewal proposal addresses early environmental signals that influence cognitive and emotional outcomes and the mechanisms by which these signals modulate the development of brain circuits underlying emotion and cognition. We have identified that patterns of maternal signals profoundly influence cognitive and emotional development: Specifically, unpredictable and fragmented patterns of maternal mood and behavior (FRAG) beginning in the fetal period increase the risk for internalizing symptoms that presage anhedonia and cognitive impairments in infancy through adolescence. Importantly, the effects of FRAG are additional to those of previously identified influences (e.g. maternal depression, anxiety, sensitivity). In this revised renewal application we benefit from Reviewer suggestions and capitalize on a cohort of children developed during the original award period for whom we have an unprecedented pre and postnatal exposure history, to test the hypothesis that FRAG is a novel form of adversity that influences mental health outcomes via aberrant maturation of brain circuits. Extending our existing cognitive and emotional assessments and considering sex and ages at exposure and assessment as important variables, we will emphasize anhedonia, a novel FRAG outcome identified across species with emerging significance as an important transdiagnostic dimensional entity in mental illness. We will examine the early manifestation of anhedonia in 3-6 year old children using a dimensional RDoC approach, determine novel maternal signals that increase risk for its expression, and identify mechanisms and biomarkers focusing, respectively, on disruption of normal brain circuit development and epigenetic signatures. Thus, we shall capitalize on our cutting edge neuroimaging, intra-individual methylomics and novel assessment tools to test the following hypotheses: (1) that early life exposure to fragmented and unpredictable maternal signals increases risk for anhedonia in 3 to 6-year-old children. (2) that exposure to a fragmented and unpredictable early life home environment increases the risk of anhedonia in 3 to 6-year-old children. (3) that early life exposure to fragmented and unpredictable maternal and environmental signals increases risk for anhedonia in early childhood through the disruption of pleasure/reward brain circuits and that methylome changes (signatures) in two paired samples from the same infant will provide predictive biomarkers of this risk.